Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis
| العنوان: | Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis |
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| المؤلفون: | Ricardo Moreno Traspas, Tze Shin Teoh, Pui-Mun Wong, Michael Maier, Crystal Y. Chia, Kenneth Lay, Nur Ain Ali, Austin Larson, Fuad Al Mutairi, Nouriya Abbas Al-Sannaa, Eissa Ali Faqeih, Majid Alfadhel, Huma Arshad Cheema, Juliette Dupont, Stéphane Bézieau, Bertrand Isidor, Dorrain Yanwen Low, Yulan Wang, Grace Tan, Poh San Lai, Hugues Piloquet, Madeleine Joubert, Hulya Kayserili, Kimberly A. Kripps, Shareef A. Nahas, Eric P. Wartchow, Mikako Warren, Gandham SriLakshmi Bhavani, Majed Dasouki, Renata Sandoval, Elisa Carvalho, Luiza Ramos, Gilda Porta, Bin Wu, Harsha Prasada Lashkari, Badr AlSaleem, Raeda M. BaAbbad, Anabela Natália Abreu Ferrão, Vasiliki Karageorgou, Natalia Ordonez-Herrera, Suliman Khan, Peter Bauer, Benjamin Cogne, Aida M. Bertoli-Avella, Marie Vincent, Katta Mohan Girisha, Bruno Reversade |
| المساهمون: | Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development |
| المصدر: | Nature genetics. Nature Publishing Group |
| بيانات النشر: | Springer Science and Business Media LLC, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Adult, Liver Cirrhosis, Liver, Tumor Suppressor Proteins, Hepatocytes, Genetics, Animals, Humans, RNA, Messenger, Syndrome, Child, Zebrafish |
| الوصف: | Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient’s primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis. |
| تدمد: | 1546-1718 1061-4036 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::747ba8cc882c52da515268747f0c3985Test https://doi.org/10.1038/s41588-022-01120-0Test |
| حقوق: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....747ba8cc882c52da515268747f0c3985 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15461718 10614036 |
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